Findings, reported in PNAS, support idea that the tau protein is involved in how the disease progresses.

Investigators at Washington University School of Medicine in St. Louis have found a genetic variation associated with an earlier age of onset in Alzheimer’s disease.


Previous work has linked genetic mutations to rare, inherited forms of early-onset Alzheimer’s disease, which can occur at the ages of 30 to 40. The variants found in the current research influence an earlier presentation of symptoms in people affected by the more common, late-onset form of the disease.


The research team analyzed DNA from 313 subjects from Washington University’s Alzheimer’s Disease Research Center (ADRC), focusing on locations in the tau gene that previously have been found to vary between people.


“We focused on this gene for two reasons: First, it codes for the tau protein that we find in neurofibrillary tangles, and secondly, some studies in the scientific literature show an association between the gene and Alzheimer’s disease, while others do not,” says principal investigator, Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig professor of genetics in psychiatry and professor of neurology.


Dr. Goate’s team found that four DNA sequence variants in the tau gene were associated with higher levels of tau protein in the cerebrospinal fluid. Then they divided patients into two groups based on whether or not they had plaques in their brains.


The investigators found that the variations in the gene are only associated with an increase in tau protein levels in the cerebrospinal fluid when amyloid plaques in the brain are present.


Dr. Goate’s group hypothesized that these variants in the tau gene would be associated with symptoms of Alzheimer’s disease showing up at a younger age. “So we went back to the ADRC’s clinical samples, and that’s exactly what we found,” she remarks. “Individuals who carry these genetic variations that lead to higher levels of tau in cerebrospinal fluid actually have an earlier age of onset than those who carry variants that are associated with lower levels of tau.”


Dr. Goate asserts that these sequence variants are not linked to risk of Alzheimer’s disease but rather to earlier cognitive problems once plaques have started to form in the brain.


These findings lend further support to the hypothesis that amyloid-beta plaques form earlier in the cascade of Alzheimer’s pathology and that the tau protein is involved in how the disease progresses, according to Dr. Goate.


The study appears in the June 10 issue of Proceedings of the National Academy of Sciences (PNAS).

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